Currently the identity of precursors of the mesenchymal cells involved in wound healing and fibrosis are under debate. We propose a novel paradigm in which these cells descend from a unique subpopulation of repair progenitor cells that coexist normally with the cells of epithelial tissues. We have shown the presence of these repair cells in the lens and cornea. In the lens these repair progenitor cells rapidly respond to injury by expanding their population size through a mechanism independent of DNA replication, but likely related to their unusual characteristic of polyploidy. The signals that mediate the expansion of the progenitor cells, their reprogramming to a repair phenotype and the rapid targeting of the repair cells to the wound edge are unknown. While the repair cells function at the site of injury as regulators of the healing process, they also have the potential to transdifferentiate to a myofibroblast phenotype, the cell type linked to fibrosis. This proposal examines this novel wound healing paradigm in both lens and cornea injury models with the following questions: 1) Are the repair progenitor cells novel descendents of a hematopoietic lineage?;2) What is the mechanism by which repair cell progenitors rapidly expand in response to injury of their host epithelium?;3) How are mesenchymal progenitor cells signaled to migrate to the wound edge?;4) What is the fate of the mesenchymal cells after they complete their job of regulating wound repair?;and 5) What are the conditions that induce the repair cells to acquire the mature myofibroblast phenotype associated with disease states such as fibrosis? These studies are expected to have a major impact in the fields of cell biology and wound healing by shifting the study of the regulators of wound healing and source of myofibroblasts to this novel progenitor population.

Public Health Relevance

The knowledge gained from our studies of a novel population of progenitor cells, innate to epithelial tissues, that upon wounding are activated to form the repair cells that modulate the wound response, is expected to reveal novel targets for enhancing wound repair and tissue regeneration. Furthermore, our findings that the progeny of these cells also are a principal source of myofibroblasts, a cell type associated with fibrotic diseases such as PCO and corneal scarring, suggest that the results of our studies also will have a major impact on understanding of mechanisms of disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY021784-01
Application #
8161860
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Araj, Houmam H
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2011-09-30
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$407,852
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Walker, J L; Bleaken, B M; Romisher, A R et al. (2018) In wound repair vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype. Mol Biol Cell 29:1555-1570
Stepp, Mary Ann; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2018) Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice. Exp Eye Res 169:91-98
Stepp, Mary Ann; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2018) Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome. Int J Mol Sci 19:
Logan, Caitlin M; Bowen, Caitlin J; Menko, A Sue (2017) Induction of Immune Surveillance of the Dysmorphogenic Lens. Sci Rep 7:16235
Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2016) K14?+?compound niches are present on the mouse cornea early after birth and expand after debridement wounds. Dev Dyn 245:132-43
Pal-Ghosh, Sonali; Pajoohesh-Ganji, Ahdeah; Tadvalkar, Gauri et al. (2016) Topical Mitomycin-C enhances subbasal nerve regeneration and reduces erosion frequency in the debridement wounded mouse cornea. Exp Eye Res 146:361-9
Bleaken, Brigid M; Menko, A Sue; Walker, Janice L (2016) Cells activated for wound repair have the potential to direct collective invasion of an epithelium. Mol Biol Cell 27:451-65
Walker, Janice L; Bleaken, Brigid M; Wolff, Iris M et al. (2015) Establishment of a Clinically Relevant Ex Vivo Mock Cataract Surgery Model for Investigating Epithelial Wound Repair in a Native Microenvironment. J Vis Exp :e52886
Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2015) Partial denervation of sub-basal axons persists following debridement wounds to the mouse cornea. Lab Invest 95:1305-18
Menko, A S; Bleaken, B M; Libowitz, A A et al. (2014) A central role for vimentin in regulating repair function during healing of the lens epithelium. Mol Biol Cell 25:776-90

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